Transdermal delivery of a treatment substance is localized, non-invasive, and has the potential for sustained and controlled release of various substances, including, for example, drugs and other molecules. In addition, transdermal delivery avoids first-pass metabolism, which reduces the concentration of certain substances before the substance reaches the circulatory system. In addition, percutaneous absorption can minimize the risk of irritation of the gastrointestinal tract and minimize pain and other complications associated with parenteral administration.
Transdermal delivery, however, requires molecules to pass through the skin. The outer layer of the skin is the stratum corneum (“SC”). The SC is composed of dead, flattened, keratin-rich cells, called corneocytes. These dense cells are surrounded by a complex mixture of intercellular lipids—namely, ceramides, free fatty acids, cholesterol and cholesterol sulfate. The predominant diffusional path for a molecule crossing the SC appears to be intercellular. The remaining layers of the skin are the epidermis (viable epidermis), the dermis, and the subcutaneous tissue.
Only a small percentage of substances or compounds can be delivered transdermally because skin has barrier properties, namely the highly lipophilic SC, that prevents molecules from penetrating the skin. As a result, only, molecules with a molecular weight (MW) of less than 500 Dalton can be administered topically or percutaneously. Often, for pharmaceutical applications, the development of innovative compounds is restricted to a MW of less than 500 Dalton when topical dermatological therapy, percutaneous systemic therapy or vaccination is the objective. In addition, transport of most drugs across the skin is very slow, and lag times to reach steady-state fluxes are measured in hours. Achievement of a therapeutically effective drug level is therefore difficult without artificially enhancing skin permeation.
A number of chemical and physical enhancement techniques have been developed in an attempt to compromise the skin barrier function in a reversible manner. These attempts may be classified as passive and active methods.
Passive methods for enhancing transdermal drug delivery include the use of vehicles such as ointments, creams, gels and passive patch technology. In addition, there are other passive methods that artificially damage the barrier in order to allow improved permeation of active substances, such as, for example, micro-needles that produce small physical holes having a depth of approximately 100-200 μm in the skin to allow improved permeation. The amount of substance that can be delivered using these methods is limited because the barrier properties of the skin are not fundamentally changed.
Current or other mode of delivery techniques may include injection using a needle, administering drugs through the skin via electroporation, and administering drugs using microneedles. Needles have the disadvantage of being painful and are invasive to the skin. Electroporation is both painful and invasive. Other attempts to enhance transdermal drug delivery, including using sonoporation, iontophoresis, etc., have inherent limitations as well, including, for example, long lag times to reach therapeutic levels or are limited by the physicochemical properties of the drug being delivered. Active methods for enhancing transdermal drug delivery systems involve the use of external energy to act as a driving force and/or act to reduce the SC barrier resistance and enhance permeation of drug molecules into the skin. Iontophoresis and electroporation are two common methods of active transdermal drug delivery systems.
Iontophoresis is the process of increasing the permeation of charged or polar drugs into skin by the application of an electric current. The amount of a compound delivered is directly proportional to the quantity of charge passed; i.e., it depends on the applied current, the duration of current application and the surface area of the skin in contact with the active electrode compartment. Advantages of iontophoresis include an improved onset time and also a more rapid offset time—that is, once the current is switched off, there is no further transportation of the compound.
To deliver drugs using iontophoresis, a drug is applied under an electrode of the same charge as the drug and return electrode having an opposite charge is placed on the body surface. A current below the level of the patient's pain threshold is applied for an appropriate length of time. Because like charges repel one another, the electrical current increases the permeation of the drug into surface tissues, without altering the structure of the SC. Iontophoresis transports drugs primarily through existing pathways in skin, such as hair follicles and sweat glands. Iontophoresis is typically used when a low level delivery is desired over a long time period. Iontophoresis involves the use of relatively low transdermal voltages (<100 V). Iontophoresis cannot be used to deliver molecules or drugs that do not carry a charge.
Transdermal absorption of drugs through iontophoresis is affected by drug concentration, polarity of drugs, pH of donor solution, ionic competition, ionic strength, electrode polarity, etc. Iontophoresis has safety concerns due to the use of electrical contacts on the skin, which may result in patient discomfort, pain and, sometimes, even skin damage and burns.
Electroporation is a method for transdermal drug delivery that consists of applying high-voltage pulses to skin. The applied high-voltage plays a dual role. First, it creates new pathways for enhancing drug permeability and second, it provides an electrical force for driving like charged molecules through the newly created pores. Electroporation is usually used on the unilamellar phospholipid bilayers of cell membranes. However, it has been demonstrated that electroporation of skin is feasible, even though the SC contains multilamellar, intercellular lipid bilayers with phospholipids and no living cells.
Electroporation of skin requires high transdermal voltages (˜100 V or more, usually >100 V). In transdermal electroporation, the predominant voltage drop of an applied electric pulse to the skin develops across the SC. This voltage distribution causes electric breakdown (electroporation) of the SC. If the voltage of the applied pulses exceeds a voltage threshold of about 75 to 100 V, micro channels or “local transport regions” are created through the breakdown sites of the SC.
DNA introduction is the most common use for electroporation. Electroporation of isolated cells has also been used for (1) introduction of enzymes, antibodies, and other biochemical reagents for intracellular assays; (2) selective biochemical loading of one size cell in the presence of many smaller cells; (3) introduction of virus and other particles; (4) cell killing under nontoxic conditions; and (5) insertion of membrane macromolecules into the cell membrane.
The presence of electrodes in contact with skin/tissue (or inserted into skin/tissue) and the delivery of current into skin/tissue in this manner leads to patient discomfort, muscle contractions, moderate to severe pain and, sometimes, even skin damage and burns. In addition, electroporation often takes hours, e.g., 6 to 24 hours, to drive therapeutic amount of drugs or other molecules transdermally.
U.S. Pat. No. 8,455,228, entitled “Method to Facilitate Directed Delivery and Electroporation Using a Charged Steam,” state that “the method and apparatus in accordance with the present invention are effective in using an electrical field to adjust the electrochemical potential of a target molecule thereby providing molecular transport of the target molecule into and/or across the tissue by a diffusive transport mechanism.” The '228 patent discloses a first embodiment with dielectric properties to assure that it will hold a charge sufficient to polarize charged entities contained within a vessel and a plurality of electroporation applicators. The process described in the '228 patent disclosure suffers from several deficiencies. First, it requires molecules that may be polarized or charged, second it requires electroporation applicators, and third, the molecule is contacted with plasma during the process, which may irreversibly modify the molecular structure leading to adverse results. In addition it is well known that interaction of molecules with plasma leads to the oxidation of such molecules, which may irreversibly alter the structure and function of the molecules.
The '228 patent also discloses a second embodiment utilizing a plasma jet with a ground ring around an inner chamber. The disclosure related to this device includes containing cells suspended in fluid in the inner chamber and promoting uptake into the cells; or injecting plasmid intradermally and exposing the injection site to plasma.
US patent publication No. 2014/0188071 discloses a method of applying a substance to the skin and applying plasma to the same area. The '071 publication discloses an open cell foam to hold a drug, water, etc., and applies plasma through the open cell foam. Applying plasma through the open cell foam and contacting the drugs with plasma may irreversibly alter the molecular structure and/or function of the drugs and cause undesirable side effects and/or render the drug ineffective.
US patent publication 2012/0288934 discloses a plasma jet and the active substance is applied to the skin with the gas stream of the plasma jet and is transported onto the region of the living cells through the barrier door that has been opened by the plasma. Applying the active substance with the gas stream of the plasma jet may irreversibly alter the molecular structure and/or function of the active substance and cause undesirable side effects and/or render the active substance ineffective.